Mechanisms and consequences of subcellular<scp>RNA</scp>localization across diverse cell types

Engel, Krysta; Arora, Ankita; Goering, Raeann; Lo, Hei‐Yong G.; Taliaferro, J. Matthew

doi:10.1111/tra.12730

Cited by 64 publications

(61 citation statements)

References 229 publications

(220 reference statements)

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“…6.2 | Alternative 3 0 -UTRs define mRNA subcellular localization The 3 0 -UTR mediates mRNA localization through binding of RBPs that interact with the components of the transport machinery, such as motor proteins and adaptors, and move their cognate mRNAs along the cytoskeleton to different cellular sub-compartments [reviewed in Czaplinski (2014) and Engel et al (2020)]. This differential localization of mRNA isoforms with alternative 3 0 -UTRs is particularly relevant in polarized cells such as neurons.…”

Section: Biological Functions Of Alternative 3 0 -Utrsmentioning

confidence: 99%

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Pereira-Castro

Moreira

2021

WIREs RNA

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Messanger RNA (mRNA) isoforms with alternative 3 0 -untranslated regions (3 0 -UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine-tunes gene expression in a cell-type-and cellular state-dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre-mRNA and is controlled by multiple regulatory determinants, including transcription, pre-mRNA cis-regulatory sequences, and protein factors. Alternative 3 0 -UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell.Genome-wide studies illustrated the full extent of APA prevalence and revealed that specific 3 0 -UTR profiles are associated with particular cellular states and diseases. Generally, short 3 0 -UTRs are associated with proliferative and cancer cells, and long 3 0 -UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single-cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3 0 -UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools.

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Section: Biological Functions Of Alternative 3 0 -Utrsmentioning

confidence: 99%

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Pereira-Castro

Moreira

2021

WIREs RNA

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“…Also, other proteins described to be involved in these RNA related processes have been linked to human disorders. Examples are different Kinesin motors, Ataxin-2, MBNL, and TDP-43, among others ( Wang et al, 2016 ; Engel et al, 2020 ; Kalantari and Filges, 2020 ; Zhao et al, 2020 ). Nevertheless, it should be taken into account that PURA is ubiquitously expressed in the human body and might fulfill important functions in a range of different tissues (Human Protein Atlas, available from http://www.proteinatlas.org ; Uhlen et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Molecular Function of PURA and Its Implications in Neurological Diseases

et al. 2021

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In recent years, genome-wide analyses of patients have resulted in the identification of a number of neurodevelopmental disorders. Several of them are caused by mutations in genes that encode for RNA-binding proteins. One of these genes is PURA, for which in 2014 mutations have been shown to cause the neurodevelopmental disorder PURA syndrome. Besides intellectual disability (ID), patients develop a variety of symptoms, including hypotonia, metabolic abnormalities as well as epileptic seizures. This review aims to provide a comprehensive assessment of research of the last 30 years on PURA and its recently discovered involvement in neuropathological abnormalities. Being a DNA- and RNA-binding protein, PURA has been implicated in transcriptional control as well as in cytoplasmic RNA localization. Molecular interactions are described and rated according to their validation state as physiological targets. This information will be put into perspective with available structural and biophysical insights on PURA’s molecular functions. Two different knock-out mouse models have been reported with partially contradicting observations. They are compared and put into context with cell biological observations and patient-derived information. In addition to PURA syndrome, the PURA protein has been found in pathological, RNA-containing foci of patients with the RNA-repeat expansion diseases such as fragile X-associated tremor ataxia syndrome (FXTAS) and amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) spectrum disorder. We discuss the potential role of PURA in these neurodegenerative disorders and existing evidence that PURA might act as a neuroprotective factor. In summary, this review aims at informing researchers as well as clinicians on our current knowledge of PURA’s molecular and cellular functions as well as its implications in very different neuronal disorders.

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“…Mislocalization of these RNAs often results in cellular or organismal phenotypes, underscoring the importance of the process (Ephrussi and Lehmann, 1992;Ghosh et al, 2012;Long et al, 1997). RNAs are often trafficked to their destination through the action of RNA binding proteins (RBPs) that bind specific cis sequence elements, usually in the 3′ UTR, and mediate transport (Engel et al, 2020;Martin and Ephrussi, 2009). However, for most localized RNAs the identity of the cis-elements and trans-acting RBPs are unknown.…”

Section: Introductionmentioning

confidence: 99%

Analysis of subcellular transcriptomes by RNA proximity labeling with Halo-seq

Goering

et al. 2021

Preprint

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Thousands of RNA species display nonuniform distribution within cells. However, quantification of the spatial patterns adopted by individual RNAs remains difficult, in part by a lack of quantitative tools for subcellular transcriptome analysis. In this study, we describe an RNA proximity labeling method that facilitates the quantification of subcellular RNA populations with high spatial specificity. This method, termed Halo-seq, pairs a light-activatable, radical generating small molecule with highly efficient Click chemistry to efficiently label and purify spatially defined RNA samples. We compared Halo-seq with previously reported similar methods and found that Halo-seq displayed a higher efficiency of RNA labeling, indicating that it is well suited to the investigation of small, precisely localized RNA populations. We then used Halo-seq to quantify nuclear, nucleolar, and cytoplasmic transcriptomes, characterize their dynamic nature following perturbation, and identify RNA sequence features associated with their composition. Specifically, we found that RNAs containing AU-rich elements are relatively enriched in the nucleus. This enrichment becomes stronger upon treatment with the nuclear export inhibitor leptomycin B, both expanding the role of HuR in RNA export and generating a comprehensive set of transcripts whose export from the nucleus depends on HuR.

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Mechanisms and consequences of subcellularRNAlocalization across diverse cell types

Cited by 64 publications

References 229 publications

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

The Molecular Function of PURA and Its Implications in Neurological Diseases

Analysis of subcellular transcriptomes by RNA proximity labeling with Halo-seq

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